The present invention relates to animals exhibiting PTSD like behavior, methods for production of same and methods for screening a candidate compound for PTSD treatment employing same and, more particularly, to a selected subset of non human animals which have been repeatedly exposed to a trauma.
Post-traumatic stress disorder (PTSD) is a common condition, which affects about 6% of the general population and has severe impact on the quality of life (Kessler et al., 1995). PTSD is an anxiety disorder that is developed by some individuals following the experience or witnessing of life-threatening events. PTSD is currently defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyper-arousal, which persist for at least one month, in survivors of a traumatic event (American Psychiatric Association, 1994).
The search for a safe and effective drug to treat of PTSD continues. Currently sertraline, a selective serotonin re-uptake inhibitor is approved for use in PTSD treatment full remission is not reported as a result of its use (Brady et al., 1995).
Abnormal activity of the autonomic nervous system (ANS) (Stein et al., 2000) and of the hypothalamic-pituitary-adrenal (HPA) axis (Yehuda et al. 1991) have been suggested as the basis of some of the characteristic behavioral features of PTSD. However, the findings concerning adrenocortical dysfunction in PTSD patients remain unclear. Pitman and Orr (1990) reported high 24-hour urinary cortisol in veterans with PTSD compared to normal controls with combat experience. Conversely, four studies reported lower 24-hour urinary cortisol in PTSD patients compared to normal controls, and to depressed patients (Yehuda et al. 1990). Young et al. (1995) reported enhanced pituitary proopiomelanocortin (POMC) messenger ribonucleic acid (mRNA) expression and corticotropin (ACTH) storage. Kosten et al. (1997) also reported elevated epinephrine level during PTSD patients as compared to major depressive disorder, paranoid schizophrenia and undifferentiated schizophrenia. As a result, there is no widely accepted biochemical parameter which could be used for rapid objective screening of the effect of a candidate compound on PTSD patients. This means that candidate compounds must be assayed on human PTSD patients followed by analysis of subjective evaluation of relief of behavioral symptoms.
While a number of animal models of PTSD have been suggested, none of these models address the well-accepted clinical findings that only a minority (about 20%) of individuals exposed to a traumatic event will eventually develop PTSD. For example, Cohen et al. (Biol Psychiatry. 2003 Mar. 15; 53(6):463-73), propose a model which relies upon a single 10-min exposure to a predator and arbitrarily selected cutoff behavioral criteria (CBC). This article makes no attempt to determine which animals will have a traumatic response when confronted with a stimulus related to the original trauma.
WO 200191548 teaches a transgenic animal model with a Wolfram Syndrome 1 (WFS1) transgene. The model is employed for evaluation of antidepressant drugs. This model has, an inherent disadvantage a strict dependence on a pre-selected biological parameter. Further, assay of efficacy of candidate compounds is neither taught nor fairly suggested. Further, a potential role for the Wolframin gene in PTSD is neither taught nor fairly suggested.
Similarly, while many candidate compounds for PTSD treatment such as PKB activators (see, for example, WO 03/074046), EP1 agonists (see, for example, WO 02/0765053), and topiramate and related sulfamates (see, for example, U.S. Pat. No. 6,486,198) are reported in the literature, reports of effective in vivo screening are less frequent owing to the absence of a reliable animal model. Thus, there is a strong possibility that a known compound has potential utility in treatment of PTSD but that the difficulty associated with screening of candidate compounds will preclude its “discovery” as a PTSD treatment.
There is thus a widely recognized need for, and it would be highly advantageous to have, animals exhibiting PTSD like behavior, methods for production of same and methods for screening a candidate compound for PTSD treatment employing same devoid of the above limitation(s).